Antibacterial Treatment and Outcomes in Adults With Virus-Positive Community-Acquired Pneumonia

Rationale. Guidelines disagree on antibacterial treatment for adults with community-acquired pneumonia and a positive respiratory viral test, particularly hospitalized patients and outpatients with comorbidities. Objectives. To estimate associations between antibacterial treatment selected for community-acquired pneumonia and outcomes in adults with virus-positive, imaging-evaluated nonsevere pneumonia. Methods. We conducted a retrospective multicenter study using Epic Cosmos data from 2016-2025. Hospitalized patients treated empirically by 24 hours were compared by continuation during hours 24-48; outpatients were compared by prescription at emergency-department discharge. Analyses were stratified by guideline-defined comorbidity and used propensity-score overlap weighting with source-cluster bootstrap confidence intervals. Exploratory analyses assessed respiratory virus, antiviral treatment, antibacterial class, and outpatient timing. Measurements and Main Results. The cohort included 376,320 adults: 275,604 inpatients and 100,716 outpatients. Inpatients who continued treatment had higher 30-day adverse-event risk without guideline comorbidity (adjusted risk difference, 1.70 percentage points; 95% confidence interval, 0.80-2.39) and with guideline comorbidity (2.56; 1.88-3.14), and longer post-landmark stay (adjusted mean ratios, 1.14 and 1.08). Exploratory class-specific analyses showed the largest adverse-event and mortality associations with broad therapy targeting resistant staphylococci or Pseudomonas; macrolide-containing and other atypical coverage showed no consistent adverse signal. Outpatient prescribing was associated with lower risks, but care-transition and residual confounding remained. Conclusions. Continued inpatient therapy after the empiric period showed no evidence of benefit and was associated with worse observed outcomes. Outpatient associations favored prescribing but remained vulnerable to care-transition and residual confounding.